JP2019112468A - Methods of delivering cromolyn - Google Patents

Abstract

To provide improved methods and compositions for delivering cromolyn via inhalation, efficiently and consistently over a prescribed range of inspiratory flow rates.SOLUTION: The invention provides methods of delivering cromolyn to a patient in need of cromolyn, methods of treating amyloid-associated conditions and inflammatory or allergic lung diseases, and blister packs and kits comprising cromolyn.SELECTED DRAWING: None

Description

This application claims the benefit of US Provisional Patent Application No. 61 / 826,798, filed May 23, 2013, which is incorporated herein in its entirety.

  The present invention relates generally to methods of delivering cromolyn to patients in need of cromolyn, methods of treating amyloid related diseases and inflammatory or allergic lung disease, and blister packs and kits comprising cromolyn.

  The use of cromolyn (also known as cromoglycate, cromoglycate or cromoglycate) for asthma is already approved. The approved form is available as cromolyn sodium (also known as disodium cromophosphate or DSCG) which is in the form of the disodium salt. Cromolyn is poorly absorbed even by oral administration. Delivery of cromolyn by inhalation has proven inefficient and difficult, due at least in part to the hygroscopicity of cromolyn sodium. For example, particulate powders containing cromolyn sodium particles are hygroscopic and thus hydrate and swell, thereby impairing efficient delivery of the cromolyn powder. See Keller et al. Expert Opin. Drug Deliv. 8, 1-17 (2011) (Non-Patent Document 1). In addition, the performance and efficiency of previously used inhalers are highly dependent on the patient's inspiratory flow rate, resulting in large variations in the amount of cromolyn sodium delivered to the patient. See Richards et al., Journal of Pharmacology and Experimental Therapeutics, 241, 1028-1032 (1987).

U.S. Patent No. 6,026,809 U.S. Patent No. 7,318,434 U.S. Patent No. 7,334,577 U.S. Patent No. 7,779,837 U.S. Patent No. 8,322,338 U.S. Pat. No. 8,371,294 U.S. Patent Application Publication No. 2009/0090361 US Patent Application Publication No. 2010/0294278 U.S. Patent Application Publication 2012/0077786 International Publication No. WO 2005/076872 European Patent No. 0591136 B1 U.S. Pat. No. 8,263,645 U.S. Patent Application Publication No. 2007/0193577 U.S. Patent Application Publication No. 2009/0118249 U.S. Patent Application Publication 2012/0118991 U.S. Pat. No. 5,497,763 U.S. Patent No. 7,080,644 U.S. Patent No. 7,828,150 U.S. Patent No. 7,931,022 U.S. Patent No. 8,291,900 International Publication No. WO 1999/23180 International Publication No. WO 1989/01348

Keller et al. Expert Opin. Drug Deliv. 8, 1-17 (2011) Richards et al., Journal of Pharmacology and Experimental Therapeutics, 241, 1028-1032 (1987) Chow et al., "Particle Engineering for Pulmonary Drug Delivery," Pharm. Res., 24 (3), 411-437 (2007) Mitchell and Nagel, "Particle Size Analysis of Aerosols from Medicinal Inhalers," KONA, 22, 32-65 (2004) Eisenberg and Jucker, Cell, 148, 1188-1203 (2012) Baltes et al., Methods Mol Biol., 711, 511-33 (2011) Kepe et al., Methods Enzymol., 412, 144-60 (2006) Burnham et al., "A blood-based predictor for neocortical Aβ burden in Alzheimer's disease: results from the AIBL study," Molecular Psychiatry (April 2013)

  The present invention provides improved methods and compositions for delivering cromolyn efficiently and consistently by inhalation over a given inspiratory flow rate range.

  The present invention provides a method of delivering cromolyn to a patient in need of cromolyn. Patients in need of cromolyn include those in need of systemic delivery of cromolyn (eg, delivery to brain or other non-pulmonary tissues). In an exemplary embodiment, a patient in need of cromolyn has an amyloid related disease. Also, patients in need of cromolyn also include patients in need of pulmonary delivery of cromolyn for lung or airway related diseases. In an exemplary embodiment, the patient in need of cromolyn has an inflammatory or allergic lung disease such as asthma.

  The method comprises orally inhaling to the patient a pharmaceutically acceptable salt or ester of cromolyn in the form of a powder comprising particles of the pharmaceutically acceptable salt or ester of cromolyn. The particles have a mass median aerodynamic diameter (MMAD) of about 1 to 4 microns. The powder is (a) at least 1.5 mg and (b) at least at Stage 4 or higher of the Next Generation Pharmaceutical Impactor (NGI) cascade impactor apparatus with a flow rate of 30 L / min and a time of about 4 seconds. The patient is administered using a device configured to deposit 30% by weight of a pharmaceutically acceptable salt or ester of cromolyn.

  In a related method, the present invention is a method of delivering cromolyn to a patient in need of cromolyn comprising: (a) at least 1.5 mg and (b) at least 30% by weight of the dose of cromolyn pharmaceutically acceptable. Also provided is a method comprising orally inhaling a pharmaceutically acceptable salt or ester of cromolyn in the form of a powder to the patient under conditions such that the possible salt or ester is delivered to the lower respiratory tract of the patient. . As used herein, the term "lower airway" refers to the area of the airway / lung corresponding to Stage 4 or higher of the Next Generation Pharmaceutical Impactor (NGI) cascade impactor device.

  The present invention is also a method of delivering cromolyn to a patient in need of cromolyn, comprising a chamber comprising a piezoelectric or ultrasonic transducer for disintegrating the powder and collecting the crushed powder and Pharmaceutical preparation of cromolyn with a pharmaceutically acceptable salt or ester of cromolyn using a dry powder inhaler (dry powder inhaler) (DPI) device containing an air flow path for delivery for oral inhalation to the patient There is provided a method comprising orally inhaling to a patient in the form of a powder comprising particles of a pharmaceutically acceptable salt or ester. The particles of the pharmaceutically acceptable salt or ester of cromolyn have an aerodynamic mass median diameter (MMAD) of about 1 to 4 microns.

  In various embodiments, a pharmaceutically acceptable salt or ester of cromolyn is administered to a patient at a dosage of about 3 mg to 16 mg (e.g., about 3 mg to 8 mg). Optionally, a pharmaceutically acceptable salt or ester of cromolyn is administered with one or more pharmaceutically acceptable excipients. In various embodiments, the powder comprises excipients in a proportion of about 0.1 to 80% by weight, for example about 40 to 80% by weight. In various embodiments, the excipient is a monosaccharide, disaccharide, oligosaccharide, polysaccharide or polyalcohol, such as, for example, lactose, mannitol or sorbitol.

  In addition, the present invention provides methods of treating the disease in patients with amyloid related disease. The method comprises applying a predetermined amount of a pharmaceutically acceptable salt or ester of cromolyn, in the form of a powder comprising particles having an aerodynamic mass median diameter (MMAD) of about 1 to 4 microns, at a flow rate of 30 L / min. And pharmaceutically acceptable for (a) at least 1.5 mg and (b) at least 30% w / w of the dose of cromolyn on Stage 4 or higher of the Next Generation Pharmaceutical Impactor (NGI) cascade impactor device with a time of about 4 seconds Oral inhalation administration to a patient for pulmonary delivery using a device configured to deposit possible salts or esters.

  The invention further provides a method of treating the disease in a patient with inflammatory or allergic lung disease. The method comprises administering a single dose of about a single dose of a pharmaceutically acceptable salt or ester of cromolyn in the form of a powder comprising particles optionally having an aerodynamic mass median diameter (MMAD) of about 1 to 4 microns. With 3-16 mg, include oral inhalation administration to a patient once or twice a day. The amount and / or frequency of delivery by such methods is less than conventional amounts and frequencies.

  In various embodiments of the present invention, a powder comprising particles of a pharmaceutically acceptable salt or ester of cromolyn is administered to a patient using an active dry powder inhaler. Active dry powder inhalers, for example, a chamber with a piezoelectric or ultrasonic transducer for crushing dry powder and a container for collecting and conveying the broken powder for oral inhalation to the patient A dry powder inhaler including an air flow path of

  In various embodiments, the present invention is a method for treating a disease associated with an amyloid related disease, the method comprising using a nebulizer with a liquid particle of a solution containing a pharmaceutically acceptable salt or ester of cromolyn. Providing a method comprising the step of orally inhaling to the patient. The particles have an aerodynamic mass median diameter (MMAD) of about 1 to 4 microns.

  The present invention further provides the use of a pharmaceutically acceptable salt or ester of cromolyn in an amount of about 3 to 16 mg in preparing a medicament for treating the disease in patients with inflammatory or allergic lung disease. Including. The drug for the treatment of inflammatory or allergic lung disease is orally inhaled once or twice daily, and a pharmaceutically acceptable salt or ester of cromolyn is about 1 to 4 microns aerodynamics. It is in the form of a powder comprising particles of a pharmaceutically acceptable salt or ester of cromolyn optionally having a mass median diameter (MMAD). The present invention further contemplates the use of pharmaceutically acceptable salts or esters of cromolyn in the preparation of a medicament for treating the disease in patients with amyloid related diseases. Drugs for treatment of amyloid related diseases are administered to patients by pulmonary delivery or oral inhalation. In various embodiments, a pharmaceutically acceptable salt or ester of cromolyn comprises particles of a pharmaceutically acceptable salt or ester of cromolyn having an aerodynamic mass median diameter (MMAD) of about 1 to 4 microns. It takes the form of powder containing. The agent is optionally delivered using a dry powder inhaler as described herein. Alternatively, a pharmaceutically acceptable salt or ester of cromolyn is in solution and is administered using a nebulizer.

  Furthermore, the present invention provides a blister package for delivering cromolyn to a patient in need of cromolyn. The blister pack comprises a plurality of blisters comprising about 3 to 16 mg (e.g. about 3 to 8 mg) of a pharmaceutically acceptable salt or ester of cromolyn. The invention also provides a kit comprising a blister pack as described herein and a dry powder inhaler (DPI) device. In some embodiments, the DPI device is a powder inhaler, for example, a chamber with a piezoelectric transducer for disintegrating dry powder and a device for collecting the crushed powder and for oral inhalation to a patient Such as a dry powder inhaler device including an air flow path for transport. In some embodiments, the kit further comprises ibuprofen tablets.

  Further aspects of the present invention will become apparent to those skilled in the art upon reading the following detailed description in conjunction with the appended claims. While various forms of embodiments are possible with the present invention, specific embodiments of the present invention are described below. However, it should be understood that what is disclosed herein is exemplary and that the invention is not intended to be limited to the specific embodiments described herein. It is intended that the entire specification be associated as a unitary disclosure, and even though the combination of features is not found together in the same sentence or paragraph or section of the document, the features described herein. It should be understood that all combinations of are contemplated. For example, where embodiments relating to methods of delivering cromolyn are described, embodiments involving methods of treatment, kits and the like having the same characteristics and features are specifically contemplated, and vice versa.

  In addition to the above, the invention comprises, as a further aspect, all the embodiments narrower in scope in some way than the variants specifically mentioned above. With respect to the aspects of the invention that are described as superordinate concepts, all individual subconcepts are considered individually as separate aspects of the invention. It should be understood that, for elements described as optional within a given range, all individual subunits within the range are contemplated as embodiments of the present invention. Ranges may be expressed herein as one particular value or another particular value, followed by “about” or “approximately”. When represented in such a range, another embodiment according to the present invention includes from one particular value to the other particular value. Similarly, if a particular value is expressed as an approximation, but the word "about", "at least about" or "less than about ..." is not attached, that particular value may indicate another embodiment. It should be understood to constitute.

  With respect to the aspects of the invention described or claimed using the singular, it is to be understood that these terms refer to the singular or plural unless the more restrictive meaning is explicitly required in the context. It is. The term "or" should be understood to include items alternatively or together unless the context clearly requires otherwise. Where an aspect of the invention is described as "comprising" a feature, then embodiments are also considered to be "comprising" the feature or "being substantially comprising" the feature.

  The present invention provides improved methods and compositions for efficiently and consistently delivering cromolyn by inhalation. Such methods preferably deliver uniform amounts of drug over a wide range of patient inspiratory flow rates. According to some embodiments of the method of the present invention, the majority of the dose of cromolyn mediates the transition to the systemic circulation (bronchial area, bronchial area and alveolar area), such as the lower airways. Delivered to the area. Thus, the method of the present invention provides an effective means to deliver cromolyn systemically, ie, into the bloodstream (and by spreading, to other areas of the body other than the lungs, such as the brain). be able to. The enhanced delivery efficiency associated with the methods of the present invention can reduce the dose and / or frequency of cromolyn, thereby achieving the desired biological response in any condition requiring pulmonary or systemic delivery. can do. The advantages of the present invention include the improvement of therapeutic efficacy at conventional doses, or the maintenance / improvement of therapeutic efficacy at lower doses and / or frequencies, which improve the usability. Patients' compliance with medications is improved, therapeutic efficacy is improved, and costs are reduced as drug volume is reduced. Furthermore, many of the drug packaging systems (e.g. blister packs etc) comprising groups of individual delivery units have a maximum volume of single dose of drug contained in the individual delivery units (e.g. blisters etc). Also, more efficient cromolyn delivery advantageously facilitates packaging a therapeutically effective amount of cromolyn in each of the individual delivery units. Among the advantages of the present invention are increased dose delivery per dose, uniform dose delivery in multiple dose regimens (ie, little variation between doses), and / or single dose delivery. Rather than using multiple individual delivery units, it involves the use of one individual delivery unit per dose.

  Hereinafter, the present invention will be described in more detail. Section headings are for ease of viewing and are not intended to be limiting in themselves.

Powder Administration In one aspect, the invention provides methods of delivering cromolyn to a patient in need of cromolyn. Patients in need of cromolyn include patients in need of pulmonary or systemic delivery of cromolyn, patients with amyloid related disease, as well as patients with inflammatory or allergic lung disease such as asthma. In any of the embodiments described herein, cromolyn (cromoglycic acid, cromoglycate, cromoglycate or 5,5 '-(2-hydroxypropane-1,3-diyl) )) Bis (oxy) bis (also known as 4-oxo-4H-chromen-2-carboxylic acid) can be administered as a powder comprising particles of a pharmaceutically acceptable salt or ester of cromolyn.

  Pharmaceutically acceptable salts are well known to the person skilled in the art, and addition salts of pharmaceutically acceptable inorganic and organic bases which can be formed with metals or amines such as alkali metals and alkaline earth metals or organic amines including. Also, pharmaceutically acceptable salts of compounds may be prepared with pharmaceutically acceptable cations. These salts can be prepared in situ in the administration vehicle or in the dosage form manufacturing process, or with a suitable base such as a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation. It can be prepared by separately reacting the purified compound in free acid form with ammonia, or with a pharmaceutically acceptable primary, secondary or tertiary organic amine. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkali metal cations, alkaline earth metal cations, ammonium cations and quaternary ammonium cations. Examples of metals used as cations include lithium, sodium, potassium, magnesium, ammonium, calcium, aluminum or ferric. Examples of suitable amines include ethylamine, diethylamine, piperazine, isopropylamine, trimethylamine, histidine, N, N'-dibenzylethylenediamine, chloroprocaine, choline, ethanolamine, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine And procaine. Suitable esters of cromolyn include, but are not limited to, aliphatic esters (eg, methyl esters, ethyl esters, propyl esters, butyl esters such as t-butyl esters, and pentyl esters), aryl esters (eg, Included are carboxylic acid esters of one or both of cromolyn carboxylic acids, such as phenyl esters and benzyl esters), and combinations thereof. In one example, the pharmaceutically acceptable salt of cromolyn is disodium cromophosphate.

  The pharmaceutically acceptable salts or esters of cromolyn are administered by inhalation (usually oral inhalation), but can also be administered by nasal inhalation or a combination of oral and nasal inhalation. If systemic delivery is desired, on the surface of the lungs that will deliver cromolyn to the patient's lungs by inhalation administration as described herein, allowing absorption into the blood stream (eg, bronchial, bronchioles, and In the alveoli, for example, the lower respiratory tract, a pharmaceutically acceptable salt or ester of cromolyn is deposited.

The cromolyn salt or ester particles are usually less than about 2.5 microns, less than about 2 microns, less than about 1.8 microns, less than about 1.5 microns, less than about 1.2 microns, less than about 1 micron, about 0.1 to 2 microns, about 0.5 to 2 microns, about 0.8 to 2 microns, about 1 to 2 microns, about 1.2 to 2 microns, about 1.5 to 2 microns, and / or about 1 It has a median particle size (D ₅₀ ) of 8 to 2 microns. The cromolyn salt or ester particles are optionally less than 4 microns, less than 3.9 microns, less than 3.8 microns, less than 3.7 microns, less than 3.6 microns, about 3 to 4 microns, about 3. 2 to 3.8 microns, with about 3.4 to 3.6 microns, and / or about 3.5-3.6 microns _{D 90} (i.e., particle size having 90% of particles).

  The particles of the cromolyn salt or ester have an aerodynamic mass of about 1 to 4 microns, about 1 to 3.5 microns, about 1 to 3 microns, about 1 to 2.5 microns, and / or about 1 to 2 microns. It has a median diameter (MMAD). The particles of the desired size may be obtained by any method, such as those known to those skilled in the art, including micronisation and milling. As used herein, the term "aerodynamic diameter" refers to the diameter of a unit density sphere that reaches the same velocity in a stream of air as any density non-spherical particle. As used herein, the term "aerodynamic mass median diameter" is the aerodynamic diameter in which 50% by weight of the particles have a larger diameter and 50% by weight have a smaller diameter. Point to such a diameter. Methods of determining aerodynamic diameter are known in the art and described, for example, Chow et al., "Particle Engineering for Pulmonary Drug Delivery," Pharm. Res., 24 (3), 411-437 (2007) (2007). Non-Patent Document 3).

The cromolyn salt or ester particles are usually about 1.3 to 2.5, about 1.4 to 2.4, about 1.5 to 2.3, about 1.6 to 2.2, about 1. It has a geometric standard deviation (GSD) of 7-2.1 and / or about 1.8-2. As used herein, the term "geometric standard deviation" refers to the breadth of the distribution of aerodynamic particle sizes. GSD is usually calculated as follows: GSD = (d ₈₄ / d ₁₆ ) ^1/2 . Here, d ₈₄ and d ₁₆ represent diameters such that the diameters of 84% by mass and 16% by mass, respectively, of the included aerosols are smaller than these diameters.

  The powder optionally comprises one or more pharmaceutically acceptable excipients. Suitable excipients are well tolerated by lung tissue and include, but are not limited to, monosaccharides, disaccharides, oligosaccharides, polysaccharides, polysaccharides, and combinations thereof. Exemplary excipients include, but are not limited to, lactose, mannitol, sorbitol, and combinations thereof. When a pharmaceutically acceptable excipient is present, it is usually about 0.1 to 80% by weight, about 1 to 80% by weight, about 5 to 80% by weight, about 10 to 80% by weight, about 15 to 80%. Wt%, about 20-80 wt%, about 25-80 wt%, about 30-80 wt%, about 35-80 wt%, about 40-80 wt%, about 20-75 wt%, about 20-70 wt% %, About 20 to 65% by weight, about 20 to 60% by weight, about 25 to 55% by weight, about 30 to 50% by weight, about 35 to 45% by weight, and / or about 40% by weight in the powder included. Pharmaceutically acceptable excipients can be included in anhydrous form or as hydrates, such as monohydrates or higher hydrates. The excipient optionally has a particle size of about 250 microns or less, for example about 10 to 150 microns, although other excipient particle sizes may be used in the context of the present invention.

  The particular dosing regimen for a particular patient will depend on several factors such as the condition being treated, the combination therapy being administered, the size of the patient, the frequency of administration, and the like. In various embodiments, the amount of powder administered to a patient is about 3 to 16 mg of a pharmaceutically acceptable salt or ester of cromolyn, such as about 3 to 15 mg, about 3 to 14 mg, about 3 to 13 mg, About 3 to 12 mg, about 3 to 11 mg, about 3 to 10 mg, about 3 to 9 mg, about 3 to 8 mg, about 3 to 7 mg, about 4 to 7 mg, and / or about 5 to 6 mg of cromolyn pharmaceutically acceptable Salts or esters. The amount of powder is optionally administered as a single dose or a single dose, and may be inhaled in a single breath, or inhaled in multiple breaths in the course of a single dose. Optionally, single dose or single dose powders are administered from one individual delivery unit, such as one blister or one capsule. This single dose (single dose) of powder can be repeatedly administered to the patient at any interval over the treatment period. For example, a dose of cromolyn pharmaceutically acceptable salt or ester (eg, about 3 to 16 mg) is administered to the patient once a day, twice a day, or three times a day for the duration of treatment Ru. Examples of treatment periods include at least 1, 2, 3, 4, 5, 6 or 7 days, or at least 1, 2, 3 or 4 weeks, or at least 1, 2, 3, 4, 5 or 6 months. Alternatively, a period of one year or more is included.

  Generally, administering the powder includes suspending the powder in a gas (such as air or oxygen), thereby forming an aerosol comprising the powder and the gas. Simultaneously with or after the formation of the suspension, the powder suspension is aspirated by the patient. Since the powder is usually suspended in the air stream being aspirated by the patient, the administering step includes the step of suspending the powder in the inspiratory air stream.

  Suspending the powder in a gas (such as air or oxygen) can be performed by any means, including vibrating. Shaking the powder generally aerosolizes at least a portion of the powder (ie, at least about 10%, at least about 30%, at least about 50%, at least about 75%, and / or at least about 90%). Be done. For example, vibrating the powder usually involves suspending at least a portion of the powder in a gas that is in the immediate vicinity of the powder. Furthermore, the powder comprising cromolyn and optionally a pharmaceutically acceptable excipient is an aggregate (eg, an aggregate of two or more cromolyn particles and / or an aggregate of cromolyn particles and excipient particles) May be included. While not intending to be bound by any particular theory, vibrating the powder causes the agglomerates of the particles to break up (aggregate), advantageously producing smaller particles, smaller particles Is easy to deliver to areas of the lung that allow transport into the bloodstream (eg, bronchial, bronchial and alveolar areas), such as the lower respiratory tract area. Optionally, the vibrator is vibrated and the powder is aerosolized and / or broken up by synthetic jets generated by the vibration. Methods of forming synthetic jets are described, for example, in US Pat. No. 7,318,434, which is incorporated herein by reference in its entirety. Preferably, the step of administering the powder comprises oscillating the powder at a high frequency (e.g., a frequency of about 10-50 kHz, about 15-40 kHz, and / or about 20-30 kHz).

  In various embodiments of the present invention, a powder comprising particles of a pharmaceutically acceptable salt or ester of cromolyn is applied at a flow rate of 30 L / min and a time of about 4 seconds for a next-generation pharmaceutic drug at a predetermined dose. A device configured to deposit (NGI) a pharmaceutically acceptable salt or ester of cromolyn at least 1.5 mg and (b) at least 30% by weight of the dose on stage 4 or higher of the cascade impactor device Is administered to the patient using In an exemplary embodiment, the device has at least 1 mg, at least 1.5 mg, at least 1.8 mg, at least 1 mg, at least 1.5 mg, at least 4 mg, on stage 4 or more of the NGI cascade impactor apparatus, with a flow rate of 30 L / min and a time of about 4 seconds. 2 mg, at least 2.2 mg, at least 2.5 mg, at least 2.8 mg, at least 3 mg, at least 3.2 mg, at least 3.5 mg, at least 3.8 mg, at least 4 mg, at least 4.2 mg, at least 4.5 mg, at least 4 .8 mg, at least 5 mg, at least 5.2 mg, at least 5.5 mg, about 1.3 to 3.5 mg, about 1.5 to 3 mg, about 1.5 to 5 mg, about 1.5 to 7 mg, about 1 to 3 mg About 1 to 5 mg, about 1 to 7 mg, about 1.8 to 2.8 mg, about 1.5 to 2 5 mg and / or about 2 to 2.5 mg and (b) at least 30 wt%, at least 35 wt%, at least 40 wt%, at least 45 wt%, about 30 to 75 wt%, about 30 to 65 wt% of the dose. It is configured to deposit a pharmaceutically acceptable salt or ester of cromolyn at a deposition rate of about 30 to 60%, about 30 to 55%, and / or about 30 to 50% by weight. As used herein, the term "dosage" in the expression "dose of ... wt%" is present in an individual delivery unit (e.g., blister or capsule or other unit dose container) coupled to the device. Amount of a pharmaceutically acceptable salt or ester of cromolyn. Thus, in one exemplary embodiment, the device is described herein from a blister containing 6 mg of cromolyn salt or ester ("dose") with or without excipients. Deliver at least about 1.8 mg of cromolyn salt or ester over Stage 4 or higher of the NGI cascade impactor. NGI cascade impactors are useful for examining the aerodynamic size distribution of aerosols and for simulating delivery to different areas of the lung. The airways of humans form a particle size selection system, and large particles are deposited in the mouth, and then deposited through the larynx, the larger airways, and toward the periphery of the lung (eg, alveolar cavity). It will be smaller and smaller. Similarly, cascade impactors include several "stages" and are designed such that smaller particles are collected at each stage in the order of particle size. The particles pass each stage on an aerosol stream with a constant air flow rate (e.g. 30 L / min). Particles with similar aerodynamic sizes are deposited at a particular stage, and smaller particles than relatively large particles are deposited at a further stage of the NGI cascade impactor. Operating at a flow rate of 30 L / min for a total of about 4 seconds, particles having an aerodynamic mass median diameter (MMAD) of about 4 microns or less are collected at Stage 4 or higher of the NGI cascade impactor. NGI cascade impactors are generally operated at low relative humidity conditions, for example at a relative humidity of 20% or less. The most deposited in the central (bronchial) area of the lung is generally particles having an MMAD of about 4 to 6 microns, and the most deposited in the peripheral (alveolar) area of the lung is generally , Particles having an MMAD of about 2 to 4 microns. See Mitchell and Nagel, "Particle Size Analysis of Aerosols from Medicinal Inhalers," KONA, 22, 32-65 (2004). Thus, stage 4 or higher of the NGI cascade impactor when operating at a flow rate of 30 L / min for a total of about 4 seconds mimics the area of the lung where drugs are absorbed systemically into the bloodstream. NGI cascade impactor devices are available from MSP Corporation (MSP Corporation (Shoreview, Minnesota)).

  Advantageously, the cromolyn delivery method of the present invention enables consistent active agent delivery over a wide flow rate range. For example, a uniform amount of powder is delivered to the patient at an inhalation flow rate of 20 to 100 L / min, or 20 to 80 L / min, or 20 to 60 L / min. By "uniform amount" is meant that the relative standard deviation (RSD) is 10% or less (e.g., 5% or less, 3% or less, and / or 2.5% or less) in the amount of powder received by the patient. Do.

Powder Administration Devices Devices for administering the powders described herein include, but are not limited to, dry powder inhaler (DPI) devices, metered dose inhalers (MDI) devices, and dry A powder sprayer (DPN) device is included. Suitable devices usually administer a fixed or defined dose. Such doses are usually administered over a set time or set air volume. In various embodiments, the device functions independently of the patient's inspiratory flow rate. Thus, for example, the device delivers uniform amounts of cromolyn over a broad flow rate range, such as 20 to 100 L / min, or 20 to 80 L / min, or 20 to 60 L / min.

  Optionally, the device is a dry powder inhaler comprising a chamber in fluid communication with the air flow path. The chamber contains a transducer suitable for aerosolizing and / or crushing the dry powder, such as a piezoelectric transducer or an ultrasonic transducer. The dry powder inhaler optionally comprises a lever for activating a piezoelectric or ultrasonic transducer, which cooperates with blister piercing or blister opening means.

  In one embodiment, the powder is delivered from the inhaler by receiving a blister containing the powder at a working position proximal to the piezoelectric or ultrasonic transducer. The patient places the mouthpiece of the inhaler into the mouth, covers the mouthpiece with his or her lips, and draws air through the air flow path while pushing the lever. When activated by a lever or other triggering event, the blister breaks and the piezoelectric or ultrasonic transducer is activated and the crushed powder is placed on the patient's inspiratory flow and transported through the air flow path. Inhaled by the patient.

  The inhaler optionally includes an inhalation flow rate detector that detects movement of air through the air flow path. In some embodiments, where the inhaler includes an insufflation flow rate detector, events triggering the release of powder include movement of air past the threshold velocity and through the air flow path.

  The powder is usually delivered in about 1 to 2 seconds, for example, with a total inhalation time of about 1 to 5 seconds. Inhalation time can be monitored using a visual indication (eg, flashing or changing color of a light emitting diode) or an auditory signature.

  Optionally, a flash drive or other computer that is monitored for lever, inspiratory flow rate, and operation of the piezoelectric or ultrasonic transducers and is in direct contact with the inhaler or out of the inhaler but in signal communication It is recorded in memory such as memory. For example, functional parameters of the inhaler device can be transmitted from the inhaler device to a remote location via a wired or wireless communication network, stored in memory, and provided to a healthcare provider. Also, optionally, information may be sent to the location of the care device to monitor treatment. The recorded actuation information allows medical personnel to monitor the use of the inhaler device, which reduces the patient's ability to manipulate the device due to a decline in cognitive and / or physical health. It can be particularly beneficial when

  The devices are also disclosed in U.S. Patent Nos. 6,026,809 (Patent Document 1), U.S. Patent Nos. 7,318,434 (Patent Document 2), U.S. Patent Nos. 7,334,577. (Patent Document 3), U.S. Patent No. 7,779,837 (Patent Document 4), U.S. Patent No. 8,322,338 (Patent Document 5), U.S. Patent No. 8,371,294 (Patent Document 6), US Patent Application Publication No. 2009/0090361 (Patent Document 7), US Patent Application Publication No. 2010/0294278 (Patent Document 8), US Patent Application Publication No. 2012/0077786 (Patent Document 9) , WO 2005/076872 (patent document 10), and European patent 0591136 B1 (patent document 11), which are described in their entirety. Ri is incorporated.

Solution Administration Using a Nebulizer In various embodiments, the present invention also includes a method of treating the disease, preferably in a patient with an amyloid-related disease, comprising administering cromolyn to the patient using the nebulizer. The method comprises administering, via a nebuliser, liquid particles of a solution comprising a pharmaceutically acceptable salt or ester of cromolyn via inhalation (e.g. oral inhalation) by a patient. These solution particles are droplets of a solution in which a pharmaceutically acceptable salt or ester of cromolyn and any optional excipients are dissolved. Pharmaceutically acceptable salts or esters of cromolyn are usually present in solution at a concentration of about 1 to 100 mg / mL, for example, a concentration of about 5 to 50 mg / mL and / or about 10 to 20 mg / mL. If an excipient is included, the excipient is usually present in solution at a concentration of about 1 to 100 mg / mL, for example, a concentration of about 5 to 50 mg / mL and / or about 10 to 20 mg / mL. Solution particles (i.e., droplets) are about 1 to 4 microns, for example, about 1 to 3.5 microns, about 1 to 3 microns, about 1 to 2.5 microns, about 1 to 2 microns, about 2 to 4 microns And / or have an aerodynamic mass median diameter (MMAD) of about 2.5 to 3.5 microns. Also, the solution particles (ie, droplets) are optionally less than about 2 microns, less than about 1.8 microns, less than about 1.5 microns, less than about 1.2 microns, less than about 1 micron, about 0.5 Including a median diameter of ̃2 microns, about 0.8-2 microns, about 1-2 microns, about 1.2-2 microns, about 1.5-2 microns and / or about 1.8-2 microns. The excipients, the dose, the target area of the lung, the delivery amount and the delivery efficiency, and the method of estimating the delivery to the target area of the lung have already been described.

  Suitable devices for administering cromolyn as a solution include, but are not limited to, jet, ultrasonic or electronic nebulizers. These nebulizer devices can be prepared from cromolyn (e.g., cromolyn sodium, etc.), pharmaceutically acceptable salts or esters of cromolyn aerosolized from a pharmaceutically acceptable solution (e.g., hypotonic or isotonic solution). Form particles). The nebulizer device optionally includes a liquid reservoir spaced from the mouthpiece or face mask by a vibrating mesh, piezoelectric element or compressed gas atomizer element. In such a configuration, the liquid reservoir contains a solution containing a pharmaceutically acceptable salt or ester of cromolyn, and the nebulizer device produces misty particles for oral inhalation. When using a nebulizer, the cromolyn solution is optionally delivered to the patient by inhalation (oral inhalation, nasal inhalation, or a combination thereof) for about 10 minutes or less (eg, 2 minutes).

  The nebulizer may have any of the features of the dry powder dosing device described herein. In an exemplary embodiment, the nebulizer device is at least 1 mg, at least 1.5 mg, at least 1.5 mg, at or above stage 4 of the NGI cascade impactor apparatus, with a flow rate of 30 L / min and a time of about 4 seconds (or less than about 4 seconds). 1.8 mg, at least 2 mg, at least 2.2 mg, at least 2.5 mg, at least 2.8 mg, at least 3 mg, at least 3.2 mg, at least 3.5 mg, at least 3.8 mg, at least 4 mg, at least 4.2 mg, at least 4 .5 mg, at least 4.8 mg, at least 5 mg, at least 5.2 mg, at least 5.5 mg, about 1.3 to 3.5 mg, about 1.5 to 3 mg, about 1.5 to 5 mg, about 1.5 to 7 mg , About 1 to 3 mg, about 1 to 5 mg, about 1 to 7 mg, about 1.8 to .8Mg, about 1.5-2.5, and / or pharmaceutically depositing acceptable salt or ester / delivery of cromolyn about 2～2.5Mg. In an exemplary embodiment, the nebulizer device is at least 30% by weight, at least 35% by weight, at least 40% by weight on Stage 4 or more of the NGI cascade impactor device, with a flow rate of 30 L / min and a time of about 4 seconds. %, At least 45% by weight, about 30 to 75% by weight, about 30 to 65% by weight, about 30 to 60% by weight, about 30 to 55% by weight, and / or about 30 to 50% by weight of cromolyn pharmaceutically Deposit / deliver acceptable salts or esters (as defined above).

  In addition, nebulizers are disclosed in U.S. Patent No. 8,263,645 (Patent Document 12), U.S. Patent Application Publication No. 2007/0193577 (Patent Document 13), U.S. Patent Application Publication No. 2009/0118249 (Patent Document 14) And US Patent Application Publication No. 2012/0118991 (Patent Document 15), which are incorporated by reference in their entirety.

Amyloid Related Diseases Any of the methods described herein include methods of treating the disease in a patient with an amyloid related disease. In various exemplary embodiments, the method comprises inhaling, at a predetermined dose, a powder comprising particles of a pharmaceutically acceptable salt or ester of cromolyn described herein to a patient. Including. As mentioned above, in an alternative embodiment, the method comprises inhaling particles of a solution comprising a pharmaceutically acceptable salt or ester of cromolyn with a predetermined dose to a patient using a nebulizer. Including.

  While not wishing to be bound by a particular theory, cromolyn disodium crosses the blood-brain barrier to bind to the beta-amyloid peptide and polymerizes into amyloid peptide associations and / or oligomers and higher order aggregates. It is believed to inhibit Inhibition of β-amyloid association and / or polymerization is believed to abrogate amyloid-mediated neuronal damage and promotes the removal of oligomers and / or aggregates from the brain, thereby allowing the accumulation of amyloid in the brain. May slow down, stop or lower.

  "Amyloid related disease" means a disease or a pathological disorder associated with abnormal amyloid aggregation and / or accumulation (Eisenberg and Jucker, Cell, 148, 1188-1203 (2012)). See for reference). Amyloid accumulation is associated with a wide variety of disorders ranging from neurodegenerative disorders to systemic amyloidosis to arthritis. Examples of amyloid related diseases include, but are not limited to, Alzheimer's disease (beta amyloid), dementia, type 2 diabetes (IAPP), Parkinson's disease (alpha-synuclein), idiopathic myeloma, amyloid polyneuropathy, Amyloid cardiomyopathy, systemic senile amyloidosis, transmissible spongiform encephalopathy (eg Creutzfeldt-Jakob disease) (PrPSc), Down's syndrome, Huntington's disease (huntingtin), medullary carcinoma of the thyroid (calcitonin), atherosclerosis (Apolipoprotein), rheumatoid arthritis (serum amyloid A), amyloid in the aorta (Medin), prolactinoma (prolactin), familial amyloid polyneuropathy (FAP) (transthyretin), frontotemporal lobar degeneration-tau (Tau), familial British And Danish dementia (BriPP), hereditary non-neuropathic systemic amyloidosis (lysozyme), dialysis amyloidosis (beta 2 microglobulin), Finnish amyloidosis (gelsolin), atrial amyloidosis (atrial natriuretic factor), Transthyretin familial amyloidosis (TTR), hereditary fibrinogen alpha chain amyloidosis (fibrinogen alpha chain), motor neuron disease, lattice corneal dystrophy (keratoepithelin (keratoepithelin)), amyotrophic lateral sclerosis (SOD1), And cerebral amyloid angiopathy (beta-amyloid, cystatin) (see, eg, Koo et al., PNAS, 96 (18), 9989-9990 (1999); Eisenberg and Jucker, supra). Other examples of amyloid related diseases include head trauma (traumatic brain injury), and within a few hours after traumatic brain injury, plaques of amyloid-beta are found in patients (Johnson et al. , Nature Reviews Neuroscience, 11, 361-370 (2010)).

  As used herein, "treating" and "treatment" refer to the severity and / or onset of signs or symptoms associated with a disease, such as an amyloid-related disease or an inflammatory or allergic lung disease (described below). Refers to any reduction of Thus, "treating" and "treatment" include therapeutic and prophylactic means to reduce either the indication or the symptoms. One skilled in the art will appreciate that any degree of protection from or amelioration of amyloid related diseases or symptoms associated therewith is beneficial for subjects such as human patients, to any extent. I will. For example, reduction of symptoms such as detectable amyloid plaques may be beneficial. In another example, it may also be beneficial for the level of soluble amyloid in cerebrospinal fluid to be increased from abnormally low levels to age-appropriate levels. The quality of life of the patient is improved by reducing the severity of the symptoms in the subject to any degree and / or delaying the appearance of the symptoms. Thus, the method in one aspect is performed as soon as possible after it has been determined that the subject is at risk for an amyloid related disease, or as soon as possible after the appearance of an amyloid related disease in the subject. For example, because amyloid-beta plaques develop rapidly in patients with traumatic brain injury, the prognosis may be improved by starting treatment as soon as possible after the onset of head trauma.

  Detection of the risk, onset or presence of amyloid related disease is performed using any of a number of techniques. For example, fluorescent deposits, circular dichroism, and X-ray diffraction can be used to detect amyloid deposition outside the body. For example, amyloid in biopsy tissue usually exhibits green birefringence when stained with Congo red and observed under a polarizing microscope. For example, magnetic resonance imaging (MRI) (see, for example, Baltes et al., Methods Mol Biol., 711, 511-33 (2011)) and positron emission tomography (PET) (Kepe et al. , Methods Enzymol., 412, 144-60 (2006) (Non-patent Document 7)) can be used to detect amyloid plaques in vivo. Also, many of the neurodegenerative diseases referred to herein are mental state examinations and neuropsychological examinations (e.g. evaluation of memory and problem solving ability) and blood tests (e.g. for biomarker signatures of Alzheimer's disease) It is also diagnosed by performing a blood test. See Burnham et al., "A blood-based predictor for neocortical Aβ burden in Alzheimer's disease: results from the AIBL study," Molecular Psychiatry (April 2013) (Non-patent Document 8).

Inflammatory or Allergic Lung Disease The present invention is a method of treating the disease in a patient with inflammatory or allergic lung disease, which is pharmaceutically acceptable for a predetermined amount of cromolyn described herein. There is provided a method comprising inhaling a powder comprising particles of salt or ester to a patient. The dose and / or frequency of administration by such methods is less than conventional doses and frequencies.

  Inflammatory or allergic lung diseases include asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), pulmonary fibrosis, cystic fibrosis. For example, asthma is a condition associated with inflammation and airway hyperreactivity (AHR) in the airways of the lungs. Asthma is also identified by the overproduction of mucus. Symptoms vary from person to person (eg, slight breathlessness) to severe (wheezing, dyspnea, and / or chest tightness). During an asthma attack, the inside of the airway is inflated, thereby narrowing the flow path and reducing air flow to and from the lungs. Asthma is caused or caused, for example, by infections, allergens, chemicals and fumes, pollutants, drugs, exertion, stress, and food additives. Asthma is divided into four general categories: mild and intermittent (mild symptoms up to 2 days a week), mild and persistent (more than twice a week but not daily symptoms), and month 1 1 or 2 night onsets), moderate and persistent (daily symptoms and 3 or 4 nightly symptoms daily), and severe and persistent (all day long lasting, frequent night symptoms) .

  As described herein, “treating” and “treatment” refer to any reduction in the severity and / or onset of symptoms associated with inflammatory or allergic lung disease (eg, asthma), and thus , Therapeutic means and preventive means. For example, treatment can reduce the number and / or severity of asthma attacks in patients susceptible to allergy or airways hyperreactivity. The method in one aspect is performed as soon as possible after it has been determined that the subject is at risk for inflammatory or allergic lung disease (eg, diagnosed as allergy or airways hyperreactivity), or inflammatory Alternatively, it is carried out as soon as possible after allergic lung disease (eg, asthma) appears in the subject.

Combination Therapy The pharmaceutically acceptable salt or ester of cromolyn is optionally administered with one or more additional agents. For example, for amyloid related diseases, additional anti-amyloid drugs or anti-inflammatory drugs can be administered. For inflammatory or allergic lung disease, additional anti-asthmatic or anti-inflammatory agents or other agents used to treat airway hyperreactivity can be administered.

  Additional agents are provided in any dosage form, including solid dosage forms (eg, tablets, capsules and powders) and liquid dosage forms (eg, solutions, suspensions, emulsions, syrups and elixirs) You may Additional agents may be orally administered (eg, orally or inhaled), injected (eg, intravenous, intraarterial, intramuscular, subcutaneous, intradermal, intraarticular, intrathecal, epidural, intracranial, or intraperitoneal) May be administered by any known route of administration, including buccal administration, rectal administration, topical administration, transdermal administration, intranasal administration, administration via the pulmonary route, administration by inhalation, or intraocular administration . The additional agent can be administered simultaneously or sequentially (ie, before or after) with a pharmaceutically acceptable salt or ester of cromolyn.

  Additional agents include, for example, levodopa (cinemet), anticholinergics, eldepril, steroids, antihistamines, long acting or short acting beta agonists, immunomodulators (eg omalizumab) and theophylline .

  In the case of amyloid related diseases, the additional agent may be a cholinesterase inhibitor (e.g. donepezil (Aricept (R)), rivastigmine (Ixeron (R)), galantamine (Razadine (R))) or tacrine (Cognex (Registered trademark)), an NMDA receptor antagonist (eg, memantine (Namenda®)), a gamma-secretase inhibitor (eg, LY451039 (Semagasestat, Eli Lily)), a metal ionophore (eg, PBT2 (Prana) ), Statins, and / or endocannabinoids (eg arachidonoyl ethanolamine, tetrahydrocannabinol, 2-arachidonoyl glycerol, 2-arachidonyl glyceryl ether, N-arachidonoyl-dopamine, or It can be virodamine. Examples of non-steroidal anti-inflammatory agents include, but are not limited to, ibuprofen, acetylsalicylic acid, diflunisal, salsalate, dex ibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen , Indomethacin, tolmetin, sulindac, etodolac, ciclolac, diclofenac, nabumetone, piroxicam, meloxicam, tenoxicam, loroxicam, isoloxicam, isoxicam, mefenamic acid, melfenomic acid, flufenamic acid, tolfenamic acid, celecoxib, lycoferon, lycophorophila, and Can be mentioned. Preferably, the non-steroidal anti-inflammatory agent is administered orally (by oral ingestion or inhalation). Non-steroidal anti-inflammatory agents (eg, ibuprofen) are usually about 5 to 80 mg per day, for example about 5 to 60 mg per day, about 5 to 50 mg per day, about 5 to 40 mg per day, about 5 to 5 per day It is administered at a dose of 30 mg and / or about 5 to 20 mg per day. Non-steroidal anti-inflammatory agents (eg, ibuprofen) may be administered 1 to 4 times per day, such as 1 to 2 times per day. For example, ibuprofen can be administered at a dosage of about 5 mg to 20 mg once daily.

Blister Packages and Kits The present invention further provides a blister package comprising a group of individual delivery units, for example blisters, containing pharmaceutically acceptable salts or esters of cromolyn. Blister packs are known in the art and generally include a plurality of spaced apart air bubbles or wells (collectively referred to herein as "blisters") for holding a predetermined amount of drug. Includes a solid support. The film or membrane sealing the wells is ready to be punctured or removed from the solid support so that the drug can be delivered. The specific shape, dimensional ratio, and dimensions of the blister pack and the individual blisters can be adjusted to allow for use in specific delivery devices. For example, the blister pack can optionally be provided as a coil or a circular (eg carousel type) cartridge for insertion into a dry powder inhaler, the blister being formed as an inverted cone or dome. In addition, the number of blisters (corresponding to the number of doses) may be varied.

  Blister packs are made of materials that protect the contents of the blister from environmental exposure and are suitable for use in an inhalation device for delivering cromolyn to a patient. Suitable materials include, but are not limited to, PVC (polyvinyl chloride), PVC / PVDC (polyvinylidene chloride) mixture, PE (polyethylene), PP (polypropylene), polystyrene, cellophane, polyester (eg polyester terephthalate) ), Paper, polyamide, PET (polyethylene terephthalate), COC (cyclic olefin copolymer), metal (e.g. aluminum) foils and any mixtures thereof. If desired, different materials may be laminated to form individual blisters or blister packs. For blister packaging, see, for example, US Pat. Nos. 5,497,763 (US Pat. No. 5,017,859), US Pat. Specification (Patent Document 18), U.S. Patent No. 7,931,022 (Patent Document 19), U.S. Patent No. 8,291,900 (Patent Document 20), International Publication No. WO 1999/23180 (U.S. Pat. WO-A-2007 / 01998 and WO 1989/01348 (all of which are incorporated herein by reference in their entirety, in particular with regard to the respective descriptions of blister packaging) ).

  Blister generally has a maximum volume of about 15 to 16 mg of the ingredient and is both an active ingredient (ie cromolyn or a pharmaceutically acceptable salt or ester thereof) and a pharmaceutically acceptable excipient. including.

  In a composition of the invention, the blister of the blister pack is about 3 to 16 mg of a pharmaceutically acceptable salt or ester of cromolyn, for example about 3 to 15 mg, about 3 to 14 mg, about 3 to 13 mg, about 3 to 12 mg , About 3 to 11 mg, about 3 to 10 mg, about 3 to 9 mg, about 3 to 8 mg, about 3 to 7 mg, about 4 to 7 mg, about 5 to 7 mg, and / or about 5 to 6 mg of cromolyn Contains possible salts or esters. The blister optionally contains an additional amount of a pharmaceutically acceptable excipient, along with cromolyn.

  The pharmaceutically acceptable salt or ester of cromolyn is provided in a solid dosage form, preferably provided as a powder comprising particles of the pharmaceutically acceptable salt or ester of cromolyn described herein. Ru. As mentioned above, the powder optionally comprises one or more pharmaceutically acceptable excipients. When present, the total amount of the pharmaceutically acceptable excipient is usually about 0.1 to 80% by weight, about 1 to 80% by weight, about 5 to 80% by weight, based on the powder. 10-80 wt%, about 15-80 wt%, about 20-80 wt%, about 25-80 wt%, about 30-80 wt%, about 35-80 wt%, about 40-80 wt%, about 20 ~ 75 wt%, about 20-70 wt%, about 20-65 wt%, about 20-60 wt%, about 25-55 wt%, about 30-50 wt%, about 35-45 wt%, and / or It is included to be about 40% by weight.

  Alternatively, in some embodiments herein, cromolyn is provided in liquid solution form.

  The invention further provides a kit comprising a blister pack such as the blister pack described herein and a dry powder inhaler (DPI) device. In various embodiments, the DPI device includes a chamber with a piezoelectric transducer for disintegrating dry powder, and an air flow path for collecting the disintegrated powder and delivering it for inhalation to a patient. An active dry powder inhaler device such as a dry powder inhaler device. The kit optionally comprises non-steroidal anti-inflammatory agents (eg ibuprofen, acetylsalicylic acid, diflunisal, salsalate, dex ibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin, Tolmetin, sulindac, etodolac, ketorolac, diclofenac, nabumetone, piroxicam, meloxicam, tenoxicam, droxicam, loroxicam, isoxicam, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxib, lycoferone, hyperphorin, and gonorgorgase And one or more additional drugs. Such additional agents include any known dosage forms including solid dosage forms (eg, tablets, capsules and powders) and liquid dosage forms (eg, solutions, suspensions, emulsions, syrups and elixirs) It may be provided in a dosage form.

Example 1
The Next Generation Pharmaceutical Impactor (NGI) Cascade Impactor device (MSP Corporation, Shoreview, Minnesota, US) was used to evaluate the delivery of cromolyn by four different inhaler devices.

  The delivery of cromolyn by a disposable passive dry powder inhaler device was evaluated. The passive inhaler device included an active particle dispersion mechanism (ACTIVE MESH, Aespira) with breathing activated beating of a mesh package containing the powder to be delivered.

  By mixing disodium chromophosphate (DSCG) (Cambrex) and Lactohale LH 300 lactose (Friesland Foods Domo) in an Alpine picoline high shear mixer (module Picomix) (Hosokawa Alpine, Augsburg, Germany) for 3 minutes at a speed of 4000 rpm A mixture of DSCG and lactose was made. The mixture contained DSCG: lactose at a ratio of 80:20 (wt / wt). It was also tested on pure DSCG. The sample (pure cromolyn or cromolyn: lactose mixture) was loaded into a passive dry powder inhaler device and tested with an NGI cascade impactor at a flow rate of about 100 L / min for 2.4 seconds.

The test results are shown in Table 1 below. In a passive inhaler device, only 3% of the initial dose of pure DSCG and the initial dose of the cromolyn mixture were delivered over Stage 4 of the NGI cascade impactor device.

  Evaluation of cromolyn delivery by quantitative multi-dose passive dry powder inhaler device PROHALER (Aptar) was performed. The PROHALER inhaler will deliver cromolyn more efficiently as it produces rapidly fluctuating airflow / shear and turbulence to break up particles released from the blister before the patient inhales orally. Was an early forecast. The PROHALER inhaler also included a breath-triggered single dose blister cartridge opening system.

  Two mixtures were made by mixing disodium chromolyate (DSCG) (Cambrex) and lactose monohydrate (DMV-Fonterra Excipients) (grade: Lactohale 200, 13% fine powder) at a speed of 90 rpm for 60 minutes did. Both mixtures were different in relative amounts of DSCG and lactose, and the content ratio of DSCG: lactose was 50: 50 (wt / wt) on one side and 20: 80 (wt / wt) on the other side. The mixture was filled into blister strips and then incorporated into the PROHALER inhaler device and tested with an NGI cascade impactor at a flow rate of approximately 35 L / min.

The test results are shown in Table 2 below. The release represents the total amount of DSCG injected into the NGI cascade impactor. FPF (fine particle fraction) was calculated by the following equation.
The amount of delivered particulates with FPF = 100% × delivered particulates / release particulate size less than 3 μm corresponds approximately to the amount of cromolyn delivered to Stage 4 or higher of the NGI cascade impactor device. Thus, in the PROHALER inhaler device, about 4.4% of the initial dose of the cromolyn mixture (50: 50 mix) and only about 9.6% of the initial dose of the cromolyn mixture (20: 80 mix) It was not delivered to stage 4 or more of the impactor device.

  In addition, an evaluation of cromolyn delivery by the TWISTER inhaler device (Aptar) was also performed. The TWISTER inhaler device is a capsule based dry powder inhaler. Capsules usually have a much higher drug loading capacity as compared to blisters.

  A mixture was made comprising disodium cromophosphate (DSCG) and lactose. The mixture was incorporated into a TWISTER inhaler device and tested with an NGI cascade impactor at a flow rate of approximately 30 L / min.

The test results are shown in Table 3 below. In the TWISTER inhaler device, only about 24% of the initial dose of the cromolyn mixture was delivered to Stage 4 or higher of the NGI cascade impactor device.

  An evaluation of cromolyn delivery with an active dry powder inhaler device was also performed. Active dry powder inhaler devices comprised injection molded plastic components, electronics, batteries and blisters filled with medication. Active dry powder inhalers include a lever arm that, upon actuation of the lever arm, places the blister in a position in contact with the piezoelectric transducer in the device and then punctures with a needle. Active dry powder inhalers were also equipped with an air flow sensor that automatically activated the piezoelectric transducer after the minimum inspiratory flow rate was exceeded. The powder particles were crushed by the operation of the piezoelectric vibrator, aerosolized, and out of the blister and into the inspiratory air stream. Active dry powder inhalers provided visual feedback at the start of dosing as confirmation that dosing was completed successfully, thereby facilitating improved patient compliance. Testing with similar devices and varying flow rates in the range of 20-60 L / min showed delivery of uniform amounts of drug at any flow rate.

  A mixture of DSCG and lactose monohydrate was made by mixing disodium cromophosphate (DSCG) (Cambrex) and lactose monohydrate (DFE Pharma) (grade: Lactohale LH201) for 15 minutes at a speed of 150 rpm. The mixture contained DSCG: lactose at a ratio of 60:40 (wt / wt). It was also tested on pure DSCG. The sample (pure cromolyn or cromolyn: lactose mixture) was filled into blisters, which were then incorporated into the inhaler device and tested for 2 seconds at a flow rate of about 30 L / min using an NGI cascade impactor device.

The test results are shown in Table 4 below. The amount of particulate delivered is the amount of recovered cromolyn less than 5 μm in diameter. The FPF less than 5 μm is given as a percentage of the amount of cromolyn recovered from the NGI cascade impactor device (ie, the delivered dose). In the active inhaler device, 42% of the initial dose of pure DSCG and 43% of the initial dose of the cromolyn mixture were delivered to Stage 4 or higher of the NGI cascade impactor device. Thus, in contrast to the results presented in Tables 1 to 3, the results for active dry powder inhaler devices show that more than 1.5 mg and more than 30% of the dose is at or above stage 4 of the NGI cascade impactor device To be delivered to

Claims (34)

A method of delivering cromolyn to a patient in need of cromolyn comprising
A pharmaceutically acceptable salt or ester of cromolyn, at a dosage of about 3 to 16 mg, optionally with one or more pharmaceutically acceptable excipients, about a 1 to 4 micron aerodynamic mass center In the form of a powder comprising particles having a diameter (MMAD), at a flow rate of 30 L / min and a time of about 4 seconds, on stage 4 or higher of the Next Generation Pharmaceutical Impactor (NGI) cascade impactor device: Orally inhaling said patient using a device adapted to deposit 5 mg and (b) at least 30% by weight of said dose of a pharmaceutically acceptable salt or ester of said cromolyn How to feature   Claiming comprising administering a pharmaceutically acceptable salt or ester of cromolyn in a dosage of about 3 to 8 mg, optionally with one or more pharmaceutically acceptable excipients. The method described in 1.   2. The device according to claim 1, wherein the device is selected from the group consisting of a dry powder inhaler (DPI) device, a metered dose inhaler (MDI) device, and a dry powder sprayer (DPN) device. The method described in 2.   4. A method according to any one of the preceding claims, wherein the step of administering comprises suspending the powder in the inspiratory air stream.   5. A method according to any one of the preceding claims, wherein the administering step comprises vibrating the powder at a high frequency.   6. The method of claim 5, wherein the frequency is about 10 to 50 kHz.   The device includes a chamber comprising a piezoelectric or ultrasonic transducer for crushing dry powder and an air flow path for collecting and conveying the crushed powder for inhalation to a patient A method according to claim 3, characterized in that it is a dry powder inhaler. A method of delivering cromolyn to a patient in need of cromolyn comprising
A pharmaceutically acceptable salt or ester of cromolyn, at a dosage of about 3 to 16 mg, optionally with one or more pharmaceutically acceptable excipients, about a 1 to 4 micron aerodynamic mass center In the form of a powder comprising particles having a diameter (MMAD), a chamber provided with a piezoelectric or ultrasonic transducer for disintegrating the powder and for collecting said crushed powder for inhalation into a patient Orally inhaling said patient using a dry powder inhaler device comprising an air flow path for delivery.   Claiming comprising administering a pharmaceutically acceptable salt or ester of cromolyn in a dosage of about 3 to 8 mg, optionally with one or more pharmaceutically acceptable excipients. The method described in 8.   10. A method according to any one of the preceding claims, wherein the particles have a geometric standard deviation (GSD) of about 1.3 to 2.5.   11. A method according to any one of the preceding claims, wherein the powder comprises excipients in a proportion of about 0.1 to 80% by weight.   11. Process according to any of the preceding claims, characterized in that the powder comprises excipients in a proportion of about 40-80% by weight.   The method according to claim 11 or 12, wherein the excipient is selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, polysaccharides and polyalcohols.   The method according to any one of claims 11 to 13, wherein the excipient is selected from the group consisting of lactose, mannitol and sorbitol.   15. The device according to any of the preceding claims, wherein the device delivers a uniform amount of a pharmaceutically acceptable salt or ester of said cromolyn at an oral inhalation flow rate of 20 to 100 L / min Method.   16. A method according to any one of the preceding claims, further comprising the step of administering a non-steroidal anti-inflammatory agent.   The method according to claim 16, wherein the non-steroidal anti-inflammatory agent is orally or inhaled.   18. The method of claim 16 or 17, wherein the non-steroidal anti-inflammatory agent is administered in an amount of about 5 to 80 mg daily.   The method according to any one of claims 16 to 18, wherein the non-steroidal anti-inflammatory agent is ibuprofen.   20. The method of any one of claims 16-19, wherein the non-steroidal anti-inflammatory agent is ibuprofen administered at a dose of about 5 mg to 20 mg once daily. A method of treating a disease associated with amyloid related disease, comprising
A flow rate of 30 L / min and a pharmaceutically acceptable salt or ester of cromolyn in the form of a powder comprising particles having an aerodynamic mass median diameter (MMAD) of about 1 to 4 microns, at a predetermined dose A pharmaceutically acceptable formulation of (a) at least 1.5 mg and (b) at least 30% by weight of said dose of said cromolyn on stage 4 or higher of the Next Generation Pharmaceutical Impactor (NGI) cascade impactor device with a time of 4 seconds Orally inhaling said patient for pulmonary delivery using a device configured to deposit possible salts or esters. A method of treating a disease in a patient with inflammatory or allergic lung disease, comprising
A pharmaceutically acceptable salt or ester of cromolyn, in the form of a powder comprising particles optionally having an aerodynamic mass median diameter (MMAD) of about 1 to 4 microns, with a single dose of about 3 to 16 mg Orally administering to said patient at a frequency of once or twice daily.   23. The method of claim 22, wherein the inflammatory or allergic lung disease is asthma.   The method according to claim 23, wherein the asthma is allergic asthma or exercise-induced asthma.   (A) at least 1.5 mg and (b) at least said dose of powder on stage 4 or higher of the next-generation pharmaceutical impactor (NGI) cascade impactor apparatus with a flow rate of 30 L / min and a time of about 4 seconds 23. The method according to claim 22, characterized in that it is administered to said patient using a device adapted to deposit 30% by weight of a pharmaceutically acceptable salt or ester of said cromolyn. .   26. A method according to any of claims 21-25, wherein the powder is administered to the patient using an active dry powder inhaler.   A chamber in which the powder comprises a piezoelectric or ultrasonic transducer for disintegrating dry powder and an air flow path for collecting the disintegrated powder and conveying it for oral inhalation to a patient 27. A method according to any of claims 21 to 26, wherein the method is administered to the patient using a dry powder inhaler. A method of treating a disease associated with amyloid related disease, comprising
Administering liquid particles of a solution containing a pharmaceutically acceptable salt or ester of cromolyn to the patient by oral inhalation using a nebulizer,
The method characterized in that the particles have an aerodynamic mass median diameter (MMAD) of about 1 to 4 microns. A blister package for delivering cromolyn to a patient in need thereof.
A blister package comprising a plurality of blisters comprising about 3 mg to 16 mg each of a pharmaceutically acceptable salt or ester of cromolyn.   30. The blister package of claim 29, comprising a plurality of blisters each comprising about 3 mg to 8 mg of a pharmaceutically acceptable salt or ester of cromolyn. A kit,
A blister package according to claim 29 or 30,
A kit comprising: a dry powder inhaler (DPI) device.   32. The kit of claim 31, wherein the device is an active dry powder inhaler device. The dry powder inhaler device
A chamber comprising a piezoelectric or ultrasonic transducer for disintegrating the dry powder,
33. Kit according to claim 31 or 32, characterized in that it comprises an air channel for collecting and conveying the crushed powder for oral inhalation to the patient.   34. The kit of any one of claims 31-33, further comprising an ibuprofen tablet.